Adrenal Insufficiency

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Chapter 6

Adrenal Insufficiency

Adrenal insufficiency was the first clinical disorder linked unequivocally to pathologic changes in an endocrine organ. It is characterized by impaired adrenocortical function, which causes decreased production of glucocorticoids, mineralocorticoids, and/or adrenal androgens. Primary adrenal insufficiency is caused by diseases that affect the adrenal cortex; it is uncommon, with a recorded incidence of 6 per million population per year.1,2 Although rare, if overlooked this disorder can be life threatening. Secondary adrenal insufficiency occurs as the consequence of pituitary or hypothalamic pathology and also can be due to abrupt withdrawal of long-term glucocorticoid replacement, resulting in decreased production of adrenocorticotropic hormone (ACTH) from the anterior pituitary or decreased production of cortictropin-releasing hormone (CRH) from the hypothalamus.

History

The recognition of this disease by Addison is generally accepted as the beginning of clinical endocrinology as a specialty. The adrenal glands were first recognized as organs distinct from the kidneys by Bartolomeo Eustachi in 1563.3 The clinical importance of the adrenal glands was recognized by Addison, a British surgeon, and was described in one of the classic papers in medicine.4 He showed that destruction of the adrenal glands in humans was associated with a fatal outcome. Of the 11 patients who were described, 5 had bilateral adrenal tuberculosis, 1 had unilateral adrenal tuberculosis, 3 had carcinomatous adrenal involvement, 1 had adrenal hemorrhage, and 1 showed atrophy and fibrosis. Addison’s findings were quickly confirmed by Brown-Sequard (1856),5 who verified Addison’s hypothesis in several laboratory animals and showed that bilateral adrenalectomy was a uniformly fatal intervention. The clinical syndrome was named after Addison by Trousseau in 1856.6 Osler7 attempted unsuccessfully to treat a young patient with Addison’s disease, employing a glycerine extract of fresh pig adrenals given orally. The effects were inconclusive. Wintersteiner and Pfiffner,8 Kendall,9 de Fremery and coworkers,10 and Grollman11 isolated and characterized cortisone and cortisol in the 1930s, and Sarett12 devised a partial synthesis for cortisone from deoxycholic acid in 1945. The clinical effects of cortisone soon were made apparent by the work of Hench and coworkers13 in the treatment of rheumatoid arthritis, and by Thorn and Forsham14 in the treatment of adrenal insufficiency. The role of the pituitary gland in regulating adrenal function was clarified largely by Cushing,15 and the role of the hypothalamus in regulating pituitary function was clarified by Harris16 in the 1950s. ACTH was isolated and characterized by Li and coworkers17 in 1958, and CRH, in turn, was characterized by Vale and coworkers18 in 1983. Finally, the syndrome of acute adrenal insufficiency was first recognized in a surgical patient who had atrophic adrenal glands secondary to long-standing glucocorticoid treatment in 1961 by Sampson.19

Pathogenesis

Adrenal insufficiency can be categorized into two types, depending on the locus of the pathologic lesion causing the disorder. Primary adrenal insufficiency (Addison’s disease) is caused by disordered adrenal function. It is characterized by a low cortisol production rate and a high plasma ACTH concentration. Secondary adrenal insufficiency is caused by disordered function of the hypothalamus and pituitary gland and is characterized by a low cortisol production rate and a normal or low plasma ACTH concentration. The two major adrenal steroids that play an important role in the syndromes of adrenal insufficiency are cortisol and aldosterone; both are usually deficient in primary adrenal insufficiency. In secondary adrenal insufficiency, however, only cortisol is deficient, because the adrenal gland is normal in this condition, and aldosterone is regulated primarily by the renin-angiotensin system, which is independent of the hypothalamus and the pituitary. This difference underlies the relatively different clinical presentations of primary and secondary adrenal insufficiency. The actions and mechanisms of action of glucocorticoids and mineralocorticoids are treated extensively elsewhere in this text. The actions of each class of steroid that have a role in the clinical syndromes of adrenal insufficiency, however, are limited in number. Glucocorticoid modulates ACTH secretion,20,21 maintains cardiac contractility,2224 modulates vascular response to the β-adrenoceptor agonists,25 and is required for hepatic glycogen deposition.21,26 Mineralocorticoid modulates the renal handling of sodium, potassium, and hydrogen ions, in effect promoting sodium retention at the expense of potassium and hydrogen excretion.27 Thus, glucocorticoid deficiency is clinically manifested as ACTH-mediated hyperpigmentation (if the hypothalamo-pituitary unit is normal), hypotension characterized by tachycardia, reduced stroke volume, decreased peripheral vascular resistance, and (in some cases) hypoglycemia. Mineralocorticoid deficiency is clinically manifested through isosmotic dehydration, leading to hyponatremia, hyperkalemia, and metabolic acidosis. Thus, in primary adrenal insufficiency, the combined effects of glucocorticoid and mineralocorticoid deficiency lead to orthostatic hypotension, hyponatremia, hyperkalemia, and a mild metabolic acidosis. This is associated with hyperpigmentation due to the high circulating levels of ACTH, which stimulates melanocortin-1 receptors on cutaneous melanocytes. Hyperpigmentation is evident, especially in areas of skin most exposed to increased friction, such as palmar creases, scars, knuckles, and oral mucosa. In secondary adrenal insufficiency, the isolated effects of glucocorticoid insufficiency lead to hypotension and hyponatremia. Hyponatremia occurs secondary (at least in part) to antidiuretic hormone (ADH)-mediated water retention, with normal potassium and hydrogen ion concentrations. ACTH hyperpigmentation is absent in secondary adrenal insufficiency.

Etiology

Primary Adrenal Insufficiency

Primary adrenal insufficiency has many causes; these are listed in Table 6-1.2832

Autoimmune Adrenal Insufficiency

When Thomas Addison first described this clinical syndrome, tuberculous adrenalitis was by far the most prevalent cause of adrenal insufficiency, and this remains a major cause in the developing world. In developed countries, 80% to 90% of patients with primary adrenal insufficiency have autoimmune adrenalitis, which can be isolated or seen as part of an autoimmune polyendocrine syndrome.

Autoimmune Addison’s disease involves the autoimmune destruction of the adrenal cortex and is the most common cause of idiopathic adrenal insufficiency in the developed world. The 21-hydroxylase enzyme is the major autoantigen targeted by antiadrenal autoantibodies, and 21-hydroxylase antibodies are present in more than 90% of recent-onset patients.33 It has been reported that the cumulative risk of developing autoimmune Addison’s disease in the presence of 21-hydoxylase antibodies was 48.5%.34 This cumulative risk was higher in children than in adults (100% vs. 31.9%), and a male preponderance was noted. The presence of autoantibodies against other steroidogenic enzymes, such as the cholesterol side-chain cleavage enzyme (P-450cc) and 17α-hydroxylase, does not correlate with the degree of adrenal dysfunction or the risk of progression. The cytotoxic T cell antigen (CTLA-4) gene has been suggested to play an important role in the predisposition to autoimmune Addison’s disease,35 and this locus is linked to type 1 diabetes and autoimmune thyroid disease. However, when found in isolation or in the context of autoimmune polyendocrine syndrome type II (APS II), no significant correlation with the development of Addison’s disease is apparent.

About 50% of all Addison’s patients have isolated autoimmune adrenal failure; the remainder exhibit an autoimmune polyendocrinopathy, including adrenal failure in association with other gland-specific failure. This latter syndrome has two forms, designated types I and II.36 The clinical features are summarized in Table 6-2.

Autoimmune polyendocrine syndrome type I (APS I) is also known as autoimmune polyendocrinopathy, mucocutaneous candidiasis, and ectodermal dystrophy (APCED). This is a rare monogenic autosomal recessive disease37 that is most prevalent in certain stable populations, including Finns and Iranian Jews. The gene that causes this syndrome is located on human chromosome 21q22 and encodes a novel protein known as autoimmune regulator (AIRE).38,39 AIRE is a nuclear protein that is expressed in cells of the immune system and has structural features that suggest a role as a transcription factor. To date, more than 40 mutations have been discovered in the AIRE gene in patients with APCED. The typical presentation is persistent candidal infection of the skin and mucous membranes, without features of severe systemic infection and with an average onset at 5 years of age, followed by hypoparathyroidism (8 years) and adrenal failure (12 years).40,41 Affected individuals may suffer from various other autoimmune manifestations such as type 1 diabetes, primary hypogonadism, pernicious anemia, malabsorption, hepatitis, hypothyroidism, alopecia, and vitiligo.

After diagnosis, patients with autoimmune polyendocrine syndrome type I should be closely monitored to prevent delay in diagnosis of additional autoimmune diseases, such as Addison’s disease and hypoparathyroidism (which may present during adulthood) and oral cancer, due to inadequate treatment for candidiasis.42

Recent attempts have been made to predict occurrences of the disease. In a large European cohort, APS I subjects were screened for 10 different autoantibodies, which revealed several interesting findings. First, redundancy in testing was noted for antibodies to multiple steroidogenic enzymes, and 21-hydroxylase and side-chain cleavage enzymes were deemed sufficient for the prediction of adrenocortical and gonadal failure, respectively.43 Furthermore, antibodies against tryptophan hydroxylase, which was recognized as an antigen associated with intestinal dysfunction in APS I, have now been identified as a strong predictor of autoimmune hepatitis. These advances should allow early screening for the disease and should improve early intervention rates.

Hypoparathyroidism, a hallmark of APS I, affects more than 80% of patients with this syndrome. A parathyroid-specific antigen called NACHT leucine-rich-repeat protein 5 (NALP5) has recently been identified and is highly specific to hypoparathyroidism. NALP5-specific antibodies were detected in 49% of patients with APS I with hypoparathyroidism and were absent in patients without hypoparathyroidism.44

Autoimmune polyendocrine syndrome type II presents more commonly in adulthood, mainly in the third or fourth decade, with a female-to-male ratio of 1.8 to 1.0. It is the most common of the immunoendocrinopathies, estimated at about 5 cases per 100,000 in the United States45 and 11 to 14 per 100,000 in Europe.46 It has a complex pattern of inheritance. This disorder often occurs in multiple generations of the same family, with autosomal dominant inheritance and incomplete penetrance,47 and it shows a strong association with HLA-DR3 and CTLA-4. The HLA locus plays a key role in determining T cell responses to antigens. Various alleles within the HLA-DR3/4 locus, including the DRB1*0301, DQA1*0501, DQB1*0201, and DBP1*0101 or DRB1*0404 haplotypes, have been associated with APS type II patients.48,49

The presence of autoimmune adrenal insufficiency with autoimmune thyroid disease (Schmidt’s syndrome) and/or type 1 diabetes mellitus defines APS II. Adrenal failure may precede other endocrinopathies.50 Other features (see Table 6-2) that can be part of this syndrome include hypergonadotrophic hypogonadism, vitiligo, alopecia, myasthenia gravis, pernicious anemia, celiac disease, central diabetes insipidus, and lymphocytic hypophysitis. The major distinction between APS types I and II is the absence of mucocutaneous candidiasis and hypoparathyroidism in APS type II.

X-linked polyendocrinopathy immune dysfunction and diarrhea (XPID) is a rare inborn error of immune regulation that presents as neonatal diabetes and is often fatal. The disorder is also known as X-linked autoimmunity and allergic dysregulation (XLAAD) and immune dysfunction, polyendocrinopathy, and enteropathy, X-linked (IPEX). XPID is caused by mutations in FOXP3, which is a critical determinant of CD4+ and CD25+ T regulatory cell development and function.51 It is characterized by fulminant, widespread autoimmunity, type 1 diabetes, and enteropathy, which leads to diarrhea. Immunosuppressants and bone marrow transplantation can prolong life but are rarely curative.

Infectious Adrenalitis

Infectious diseases represent the most common cause of primary adrenal failure worldwide, with generalized tuberculosis the most frequent single cause. On abdominal computed tomography (CT), an enlarged adrenal with necrotic areas can be seen in the early stages of the disease, and adrenal calcification is seen at a later stage. All the clinically important fungi except Candida can also cause adrenal insufficiency. The most common is histoplasmosis, which is particularly prominent in the Ohio and Tennessee River Valleys and along the Piedmont Plateau of the Middle Atlantic States52,53 and in South India; South American blastomycosis is the next most common fungal cause of adrenal insufficiency,54 followed by North American blastomycosis,55 coccidioidomycosis, and cryptococcosis, although all are rare causes of adrenal destruction. The pathophysiology of this process is much like that of tuberculosis, with early adrenal enlargement due to caseating granuloma formation. If healing occurs, the adrenal glands can shrink and sometimes resume a relatively normal volume. This healing process may be accompanied by calcification.

Acquired immunodeficiency syndrome (AIDS) can be associated with adrenal insufficiency in its late stages. The adrenals are involved with infection or tumor in well over half the autopsy cases, although less than 50% of the adrenal gland is destroyed in 97% of cases.56 This explains the rarity of overt symptoms. Cytomegalovirus infection of the adrenal glands is common in this condition, as is infection with Mycobacterium avium-intracellulare and the various fungi that can colonize and destroy the adrenal glands. The plasma cortisol response to ACTH administration, however, is abnormal in only 10% to 15% of these patients.57 A further occasional cause of adrenal failure is amyloidosis,58 which often is underdiagnosed and masked by other clinical manifestations of the disease. Although medications may precipitate adrenal insufficiency, they are rarely the cause (fluconazole, ketoconazole, phenytoin sodium, rifampicin, barbiturates). However, one should be aware that the anesthetic agent etomidate can cause significant adrenal insufficiency. Finally, high circulating levels of cytokines in patients with AIDS may suppress the hypothalamic-pituitary-adrenal axis without overt adrenal destruction.

Adrenal Infiltration

The adrenal glands are common sites of metastasis from several different primary tumors. Metastases to the adrenal gland can be as high as 60% in patients with disseminated breast or lung cancer. However, adrenal insufficiency as a result of metastases is uncommon,59 because clinical manifestations do not occur until more than 90% of the cortex is destroyed. Tumors that are commonly associated with adrenal insufficiency are cancers of the breast, lung, stomach, and colon; melanoma; and some lymphomas. Lymphomas in particular may be bilateral.

Adrenal Hemorrhage

With the advent of the abdominal CT, adrenal hemorrhage is recognized much more frequently as a cause of adrenal insufficiency than it was in years past. The usual setting is a stressed individual anticoagulated for the prevention of pulmonary emboli or other thrombotic phenomena. Other scenarios include trauma, sepsis, or extensive burns. A more frequently recognized relationship is that of adrenal hemorrhage and the antiphospholipid syndrome.60 It also is well recognized in children or infants with severe infection, particularly those with meningococcemia or Pseudomonas sepsis. Typically, the patient will complain of back pain, which is followed in a few days by the acute onset of the first signs and symptoms of adrenal insufficiency. Rarely, these patients may recover adrenal function.61

Genetic Disorders

Congenital adrenal hyperplasia (CAH) is a family of inborn errors of steroidogenesis, each characterized by a specific enzyme deficiency that leads to impairment of cortisol synthesis from the adrenal, and can lead to sexual ambiguity, particularly in genetic females. This autosomal recessive disease involves impaired enzymatic function at any of the various steps of synthesis of cortisol from cholesterol. Most often affected are 21-hydroxylase, 11β-hydroxylase, and 3β-hydroxylase dehydrogenase, and less often, 17α-hydroxylase/17,20-lyase and cholesterol desmolase.62 Blocks in cortisol synthesis impair the negative feedback control of ACTH secretion, and chronic stimulation of the adrenal cortex by ACTH leads to excessive secretion of androgens, resulting in altered development of primary and secondary sexual characteristics. The clinical features of the different forms of CAH are detailed extensively elsewhere in this text.

Congenital lipoid adrenal hyperplasia is a rare form of adrenal steroidogenic defect and is inherited in an autosomal recessive pattern. The disease results from mutations in the gene that encodes the steroidogenic acute regulatory protein (StAR) on chromosome 8p11, which regulates cholesterol uptake into the mitochondria in readiness for conversion to pregnenolone, the first step of steroidogenesis.63 The pathogenic mechanism has been described as a two-step process. Initially, the biallelic StAR defect leads to impaired steroid biosynthesis in both the adrenal cortex and gonads. Steroidogenesis is reduced to about 15% of normal, the residue resulting presumably because of alternative cholesterol import processes. Consequently, ACTH is stimulated, resulting in increased expression of the adrenocortical low-density lipoprotein receptor and thus increased cholesterol uptake into the adrenals. On histologic examination, the steroidogenic cells of the adrenal cortex and gonads exhibit a characteristic vacuolated appearance due to the florid lipid deposit, ultimately destroying the gland. It is the most severe form of adrenal hyperplasia; affected infants, who experience salt loss from impaired mineralocorticoid and glucocorticoid synthesis, are at risk of death, but hormonal replacement permits long-term survival. In addition, 46XY genetic males have complete lack of androgenization and appear phenotypically female owing to impaired testicular androgen secretion in utero.

Adrenoleukodystrophy (ALD) and adrenomyeloneuropathy (AMN) are two clinical presentations of the same disorder that may exhibit a very broad phenotype. ALD, also known as Brown Schilder’s disease (brown being an adjective describing the hyperpigmentation of the skin) or sudanophilic leukodystrophy, is typically a disease of children characterized by rapidly progressive central demyelination that eventuates in seizures, dementia, cortical blindness, coma, and death. Death usually occurs before puberty is complete.64,65 However, clinical manifestations can be highly variable, and long survival may occur. Adrenomyeloneuropathy is a disease of young adults that is characterized by a slowly progressive mixed motor and sensory peripheral neuropathy associated with an upper motor neuropathy, leading to an ascending spastic paraparesis. Both forms of the disease are associated with progressive failure of the steroid-secreting cells leading to adrenal and gonadal failure,66,67 but adrenal failure may occur in isolation. Usually an X-linked disorder, ALD might be underrecognized as a cause of adrenal failure. In one large series, it accounted for a significant proportion of young adult males believed to have autoimmune Addison’s disease.68 The metabolic marker for these diseases is an elevated circulating level of very long chain fatty acids (VLCFAs), C26 and greater in length, which rises in response to the primary abnormality, which is a peroxisomal defect in VLCFA metabolism. Peroxisomes are small, intracytoplasmic, membrane-enclosed bodies that contain the enzyme pathways for a number of metabolic and detoxification processes. The gene underlying ALD, identified in 1993 by positional cloning from its location on chromosome Xq28, was found to be a half-transporter of the adenosine triphosphate (ATP)-binding cassette membrane transporter class.69 It includes six transmembrane domains and an ATP-binding site. This gene probably functions as a heterodimer with another half-transporter to regulate the import of VLCFA into the peroxisome. Many missense, nonsense, and splicing defects in the ALD gene have been described in patients with this disorder. Accumulation of VLCFA in the adrenals seems to be the pathogenic mechanism, although the neuronal pathogenic process may differ. Several treatments have been tried, but only autologous bone marrow transplantation appears to be effective.70

Familial glucocorticoid deficiency (FGD) is an autosomal recessive syndrome characterized by cortisol deficiency despite high plasma ACTH and a preserved renin-aldosterone axis. Considerable phenotypic variation has been noted within this disorder. Patients with this syndrome usually present in early childhood with features of glucocorticoid deficiency with undetectable circulating cortisol, although some pass unrecognized until later childhood, and the diagnosis is then made after a short ACTH stimulation test. It is interesting to note that these children tend to be tall, for reasons that are obscure, and also tend to be highly resistant to suppression of their pigmentation in terms of hydrocortisone replacement. This latter phenomenon, which can be clinically problematic, may indicate the presence of ACTH-mediated auto-feedback at the level of the pituitary.71 The first molecular abnormality demonstrated was a mutation of the ACTH receptor, located on chromosome 18p11,72 although it is now known that these cases, known as FGD type 1, represent only some 25% of cases of FGD.72a FGD type 2 appears to relate to an entirely novel gene on chromosome 21 that encodes a single transmembrane protein called melanocortin-2 receptor accessory protein (MRAP).73 This accounts for approximately 20% of all FGD cases,74 implying that about half of all FGD cases result from other genes yet to be identified.

Triple A syndrome (Allgrove’s syndrome) is the association of alacrima, achalasia, and Addison’s disease. It is associated with a variety of progressive motor, sensory and autonomic neurologic defects plus mineralocorticoid insufficiency, and it occurs in approximately 15% of cases. This recessive condition results from abnormalities in AAAS

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